BASICS
DESCRIPTION
- Neurofibromatosis type 1 (NF1) and neurofibromatosis type 2 (NF2) are neurocutaneous syndromes (phakomatoses). Although they share a name and both are autosomal dominant disorders, they are two distinct conditions with genes on different chromosomes.
- NF2 is an autosomal dominant inherited tumor-predisposition syndrome that predisposes affected individuals to tumors of the CNS, most commonly bilateral vestibular schwannomas, leading to hearing loss and possible deafness. NF2 also predisposes patients to intracranial and spinal meningiomas.
- Synonym(s): bilateral acoustic neurofibromatosis; formerly central NF
EPIDEMIOLOGY
Incidence
Birth incidence: 1/33,000 to 40,000
Prevalence
1/60,000
ETIOLOGY AND PATHOPHYSIOLOGY
Protein product of affected gene is called "merlin " or "schwannomin " :
- Merlin is a cell-membrane " related protein.
- Merlin is the NF2 tumor suppressor, a negative regulator of mammalian target of rapamycin complex 1 (mTORC1) (1).
- Involved in interaction between actin (within the cytoskeleton) and the cell membrane; suppresses tumorigenesis through contact-mediated growth inhibition
Genetics
- Online Mendelian Inheritance in Man 101000
- Caused by a mutation in the NF2 gene on chromosome 22q12; autosomal dominant inheritance
- Penetrance is close to 100%.
- 50% of affected patients have a new mutation.
- 25 " 30% of those with no family history (simplex cases) are mosaic for disease-causing mutations.
- If there are other close family members with NF2, the affected parent has a 50% chance of transmitting the mutation to each of his or her offspring.
- Historically, two forms of disease have been described: Wishart (more aggressive, onset during late teens or early 20s) and Gardner (less aggressive and older age of onset); however, many different causative mutations have been characterized.
- Genotype " phenotype correlation:
- Mild NF2 phenotype (older age of onset, fewer tumors) associated with mosaicism, missense mutations, certain splice-site mutations, and certain large deletions
- Severe NF2 phenotype usually caused by protein-truncating mutations (frame-shift or nonsense mutations)
- Changes in the 5 " ² half of the gene have a higher risk of meningioma than do changes in the 3 " ² half.
RISK FACTORS
Having an affected first-degree relative is a diagnostic criterion.
GENERAL PREVENTION
Genetic counseling
COMMONLY ASSOCIATED CONDITIONS
- Bilateral vestibular schwannomas may be associated with tinnitus and partial hearing loss or deafness.
- Tumors
- Schwannomas of the other cranial nerves (24 " 51%)
- Schwannomas of spinal and/or peripheral nerves
- Intracranial meningiomas (45 " 58%) (including optic nerve meningiomas) and intraspinal meningiomas
- Low-grade CNS malignancies (ependymomas); rarely astrocytomas
- Intramedullary or extramedullary spinal tumors (63 " 90%)
- Neurofibromata are relatively infrequent.
- Neurologic
- Bilateral vestibular schwannomas may be associated with balance dysfunction, headache, or seizures.
- Peripheral neuropathy in up to 66% of adults; generalized polyneuropathy in 3 " 10%
- May have mononeuropathy in childhood, presenting as facial palsy, squint (CN III paralysis), foot drop, or hand drop
- Ophthalmologic
- Reduced visual acuity
- Cataracts (60 " 85%) may be the first sign of NF2 (but are rarely symptomatic), epiretinal membranes (12 " 40%), retinal hamartomas (6 " 22%)
- Dermatologic: 70% of patients have skin tumors, but only 10% have >10 tumors.
DIAGNOSIS
Manchester Diagnostic Criteria (www.nfcalifornia.org/DiagnosticNF2.aspx):
- Bilateral vestibular schwannoma or family history of NF2
- Unilateral vestibular schwannoma
- Any two of meningioma, neurofibroma, schwannoma, posterior subcapsular lenticular opacities
- Additional criteria
- Unilateral vestibular schwannoma plus any two of meningioma, glioma, neurofibroma, schwannoma, and posterior subcapsular opacities
- Multiple meningioma ( ≥2) plus unilateral vestibular schwannoma or any two of glioma, neurofibroma, schwannoma, and cataract
- Individuals who have some features of NF2 but who do not meet criteria may be mosaic for NF2 mutations and may benefit from MRI screening until pragmatic risk of NF2 falls below 1% (2)[C].
HISTORY
- Average age of onset is 18 to 24 years; 90 " 95% develop bilateral vestibular schwannomas by age 30 years.
- Most adults with NF2 presents with unilateral hearing loss.
- Cataracts, seizures, cranial meningiomas, or skin tumors may be presenting signs.
- Children may present with polio-like illness of muscle wasting in lower limbs or mononeuropathy.
PHYSICAL EXAM
- Children of affected parents: Examine for cataracts at birth.
- Formal screening starting at age 10 years
- Evaluate for hearing loss.
- Neurologic assessment should emphasize cranial nerves, balance, and coordination.
- Mononeuropathy: presenting as facial palsy, squint, hand/foot drop
- Severe polyneuropathy (independent of tumors) may result in severe muscle wasting.
- Ophthalmologic
- Visually significant cataract typically manifested as posterior subcapsular lenticular opacity.
- Epiretinal membranes
- Retinal hamartomas
- Dermatologic: The most common skin lesion is a raised intracutaneous plaque-like lesion, which is more heavily pigmented and often more hairy than surrounding skin.
DIFFERENTIAL DIAGNOSIS
- Solitary sporadic vestibular schwannoma (develops later in life and is not hereditary) (3)
- Multiple noncranial schwannomas may be seen in mosaic NF2.
- NF1:
- Lisch nodules common in NF1 are not seen in NF2.
- "Dumbbell " spinal root tumors are neurofibromas in NF1 and schwannomas in NF2.
- Schwannomatosis: Rare autosomal dominant inherited condition in which schwannomas can involve spinal roots, plexuses, and peripheral nerves but not the vestibular nerve.
- Familial multiple meningiomas: rare, unrelated condition
DIAGNOSTIC TESTS & INTERPRETATION
Initial Tests (lab, imaging)
- Molecular genetic testing will identify the genetic abnormality in >90% of families with multiple affected members.
- Genetic mosaicism may complicate diagnosis of a de novo mutation.
- MRI in patients with hearing impairment or abnormal brainstem auditory-evoked responses (BAER).
- MRI of the head should be performed by puberty in patients with NF2.
Diagnostic Procedures/Other
- Audiogram and BAER
- Tests of vestibular function may be useful adjuncts to BAER screening because VIII nerve tumors develop on the vestibular division.
- Polyneuropathy
- Nerve biopsy may show "onion bulb " in patients with neuropathy.
- Nerve conduction studies to demonstrate neuropathy
TREATMENT
- Goal of surgical treatment is preservation of function (4)[C]. Tumors may compress brainstem or cause hearing loss or facial nerve dysfunction.
- Hearing augmentation; speech therapy, as needed
- Inhibition of vascular endothelial growth factor with bevacizumab may result in shrinkage of schwannomas and improvement in hearing (5)[C] but has limited clinical use in meningiomas.
- Small clinical trials of everolimus, an oral inhibitor of the mammalian target of rapamycin complex 1 (mTORC1), yielded conflicting results in slowing the progression of vestibular schwannomas (1,6).
- Lapatinib, an EGFR/ErbB2 inhibitor, has been shown in a phase II clinical trial to have a favorable response on vestibular schwannoma volume (6).
SURGERY/OTHER PROCEDURES
- Excision of tumor; auditory implants
- Surgery may risk damage to facial nerve, which may complicate ophthalmologic problems.
- Occasionally, radiation treatment may have a role (4)[C].
ONGOING CARE
Multidisciplinary team should include a neurologist, geneticist, neurosurgeon, otolaryngologist, and neuroradiologist.
FOLLOW-UP RECOMMENDATIONS
Patient Monitoring
- Children of affected parents: Examine for cataracts at birth.
- Formal screening starting at age 10 years
- Vestibular schwannomas grow faster in younger individuals.
- MRI of head and spine: initially at age 12 years (age 10 years in individuals from severely affected families); every 2 years until age 20 years; every 3 to 5 years thereafter
- Once tumors are detected, annual MRI
- Annual audiologic tests, including auditory brainstem response
- Annual ophthalmologic evaluation
- Annual neurologic examination
- Cutaneous examination
- Poor balance, visual problems, and muscle weakness may affect mobility and necessitate the use of a wheelchair.
PATIENT EDUCATION
- Counseling and education regarding insidious problems associated with hearing loss, balance, or sense of direction
- Caution is advised when swimming, diving, or climbing heights.
PROGNOSIS
- Although prognosis is variable and unpredictable, NF2 presents substantial morbidity and has reduced life expectancy (in the 1980s, average age at death was 36 years).
- Major risk: loss of hearing and vestibular function
- Increased risk of developing intracranial and intraspinal neoplasms
- Earlier presentation has a worse prognosis.
COMPLICATIONS
- Hearing loss, vestibular dysfunction
- Intracranial neoplasms
- Vertigo, nausea, vomiting in late stage disease
- Irradiation of NF2 tumors may cause growth acceleration or transformation, especially in childhood.
REFERENCES
11 Goutagny S, Raymond E, Esposito-Farese M, et al. Phase II study of mTORC1 inhibition by everolimus in neurofibromatosis type 2 patients with growing vestibular schwannomas. J Neurooncol. 2015;122(2):313 " 320.22 Evans DG, Raymond FL, Barwell JG, et al. Genetic testing and screening of individuals at risk of NF2. Clin Genet. 2012;82(5):416 " 424.33 Evans DG, Freeman S, Gokhale C, et al. Bilateral vestibular schwannomas in older patients: NF2 or chance? J Med Genet. 2015;52(6):422 " 424.44 Evans GR, Lloyd SK, Ramsden RT. Neurofibromatosis type 2. Adv Otorhinolaryngol. 2011;70:91 " 98.55 Plotkin SR, Merker VL, Halpin C, et al. Bevacizumab for progressive vestibular schwannoma in neurofibromatosis type 2: a retrospective review of 31 patients. Otol Neurotol. 2012;33(6):1046 " 1052.66 Karajannis MA, Legault G, Hagiwara M, et al. Phase II study of everolimus in children and adults with neurofibromatosis type 2 and progressive vestibular schwannomas. Neuro Oncol. 2014;16(2):292 " 297.
ADDITIONAL READING
- Evans DG. Neurofibromatosis 2. In: GeneReviews at GeneTests Medical Genetics Information Resource (database online). Seattle, WA: University of Washington; 1993 " 2015. http://www.ncbi.nlm.nih.gov/books/NBK1201/.
- Smith MJ, Higgs JE, Bowers NL, et al. Cranial meningiomas in 411 neurofibromatosis type 2 (NF2) patients with proven gene mutations: clear positional effect of mutations, but absence of female severity effect on age at onset. J Med Genet. 2011;48(4):261 " 265.
CODES
ICD10
Q85.02 Neurofibromatosis, type 2
ICD9
237.72 Neurofibromatosis, type 2 [acoustic neurofibromatosis]
SNOMED
neurofibromatosis, type 2 (disorder)
CLINICAL PEARLS
- NF1 and NF2 are two distinct genetic disorders.
- Vestibular schwannoma should be considered NF2 until proven otherwise.
- Schwannomas of NF2 rarely (if ever) undergo malignant transformation to neurofibrosarcoma.
- Multidisciplinary management is necessary in NF2.